Only a decade has elapsed since the discovery of the novel retinal photopigment melanopsin expressed in a small subset of retinal ganglion cells, called intrinsically photosensitive retinal ganglion cells (ipRGCs). Rapid progress in this field has linked these cells to the regulation the circadian clock, the pupillary reflex, neuroendocrine secretions, and seasonal variations of mood. The canonical view has been that the functional contributions of ipRGCs are limited to these purely reflexive, homeostatic, and non-image forming roles. However, new varieties of ipRGCs have recently been discovered that send signals to brain regions involved in conscious visual perception of form, motion and color. The goal of this study is to provide the first systematic description of the form and function of these novel melanopsin-based visual channel(s) projecting to image- forming centers of the brain. Specific Aim 1 will characterize the morphology of ipRGCs projecting to two image-forming visual centers of the brain - the dorsal lateral geniculate nucleus of the thalamus (dLGN) and the superior colliculus (SC). Such structural data will permit the identification of which ipRGC subtypes participate in this channel, but will also form a crucial descriptive foundation for working out the synaptic relationships of these cells. Specific Aim 2 will characterize the physiological properties of the ipRGCs that project to the dLGN and SC. These studies will help define the unique attributes of this enigmatic perceptual channel. To identify the cells of interest, a genetically modified mouse with selective expression of GFP in ipRGCs will be used, and a contrasting retrograde axon tracer will label those that have geniculate or collicular projections. This will be just one of many techniques utilized in the pursuit of these aims, making this project an ideal training venue. Others include patch clamp recording, intracellular dye filling, immunohistochemistry, axon transport tracing, receptive field analysis, synaptic pharmacology, and confocal microscopy. These studies will provide a broader and more complete picture of the functional contribution of melanopsin and irradiance-encoding ipRGCs to normal visual perceptual mechanisms. Given the key role that ipRGCs play in the body's responses to daylight, these studies are relevant to such public health issues as jet lag, seasonal affective disorder, and alertness during shift work. In addition, this work may be shed new light on residual visual capacities in ocularly blind patients with outer retinal diseases, such as retinitis pigmentosa, age-related macular degeneration or Leber's congenital amaurosis, in which the inner retina is largely spared. New understanding of residual ganglion cell photoreception in these individuals might be harnessed to develop clinical treatments and improve lives. PUBLIC HEALTH RELEVANCE: The goal of this project is to study the structure and function of specialized output cells of the mammalian retina that can convert light energy into neural signals. Such cells have previously been thought to regulate unconscious responses to light, such as adjusting the biological clock, the levels of certain hormones, and the size of the eye's pupil. We have recently discovered new varieties of such cells that send signals to brain regions involved in conscious visual perception. Here we will provide the first systematic description of the form and function of these cells. Because of the key role these cells play in the body's responses to daylight, these studies are relevant to such public health issues as jet lag and seasonal affective disorder, as well as residual visual capacities in the ocularly blind population that can be harnessed for new clinical treatments.